Phase I study of lapatinib plus trametinib in patients with KRAS -mutant colorectal,non-small cell lung,and pancreatic cancer

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.     

Theory of mind,mental state talk and social relationships in aging: The case of friendship

Objectives: Previous research has shown a decline in Theory of mind (ToM) associated with normal aging. However, very few studies have investigated older people’s ToM using an ecological approach. The present study was designed to fill this gap and examine older people’s frequency of mental state talk (MST) in describing their best friend, together with their performance on a traditional ToM task. In addition, the study examined the association between these two ToM indices and relationships with friends and family members.

Method: Seventy-two healthy older adults (age range 60–79) participated in the study. We measured ToM ability with a classic measure, the Faux Pas task, and selected the Describe-a-friend task to measure MST frequency; social relationships were investigated with the Lubben Social Network Scale. Correlation and regression analyses were performed.

Results: No significant association between MST and scores on the Faux Pas task emerged. In addition, MST (but not Faux Pas scores) significantly predicted friendships (but not family relationships) over and above general cognitive functioning.

Conclusion: These findings show the crucial distinction between possessing an ability and using it in daily life and suggest the need to move toward more ecological measures of older adults’ abilities. In addition, the present results indicate that the spontaneous use of ToM ability, not the ability per se, impacts on older adults’ social relationships.     

Measuring female intrasexual competition by the scale for intrasexual competition: a validation of the German version

Competitive behaviour amongst members of the same sex is termed intrasexual competition. The tendency to engage in such competition appears to be strongly related to stable individual characteristics such as personality traits. Additionally, recent studies have revealed transient fluctuations in competitiveness according to the female menstrual cycle. To date, no German questionnaire exists to measure intrasexual competition. Our first study aimed to translate and validate the Intrasexual Competition Scale (ICS) by Buunk and Fisher (J Evol Psychol 7:37–48, 2009) in a population of healthy Swiss females (n = 241). Our second study applied the validated German ICS in a group of healthy, regularly cycling females (n = 49) in order to examine possible associations between the menstrual cycle phase and ICS scores. The psychometric properties suggest that the German ICS is a reliable and valid tool to assess individual differences in female intrasexual competition. Furthermore, our second study demonstrated that on average, women showed higher intrasexual competition scores when tested in the late follicular phase (M = 35.77 ± SD = 12.03) compared to the mid-luteal phase (M = 30.93 ± SD = 10.20). Our studies support previous findings of an association between ICS scores and relatively stable individual characteristics such as personality traits. Furthermore, our research endorses the assumption of cycle-dependent fluctuations in intrasexual competition. Future research should clarify the precise mechanisms underlying these findings and include biomarkers such as oestrogen and testosterone.

     

Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.     

Teen Use of Marijuana Edibles: A Focus Group Study of an Emerging Issue

Recent research indicates that marijuana-infused food product (i.e., edible) use is becoming nearly as common as smoking marijuana where medical marijuana is available. This study explores edible use among teens. We conducted four focus groups in the San Francisco Bay Area with youth, ages 15–17. The focus groups were divided by gender and whether they used marijuana. Some teens mentioned edible use at school. Youth reported that teens consume edibles, primarily to reduce the likelihood of getting caught. Edibles are also attractive to those who do not like to smoke or have concerns about smoking. Both male and female respondents suggested that females are more likely than males to prefer edibles over smoking, one reason for which may be to avoid smelling like marijuana smoke. For some young women, edibles may be a way to avoid publicly presenting themselves as marijuana users. Findings also suggest that youth have access to edibles through multiple sources. Youth reported that they can purchase edibles at school from other students who either make the edibles themselves or are reselling edibles obtained from dispensaries. Both users and non-users were aware of potentially negative consequences related to edible use. Some youth mentioned that they have heard of youth dying from edibles, and several reported being concerned about the high produced by edibles. Female non-users appeared to be more concerned than others about edibles and compared them to drinks that could be spiked with drugs. However, sentiment among some male marijuana users was that if you cannot handle edibles you should not be using them. These findings suggest that strategies to curb access to edibles and use among youth, such as restricting sales of edibles with strong youth appeal and educating youth on the risks of edibles, will need to be developed.     

Sexual Assistance in Italy: An Explorative Study on the Opinions of People with Disabilities and Would-Be Assistants

Providing assistance services for sexual activity is becoming of increasing importance to the community of people with disabilities and to mental health professionals. Nevertheless, the literature on this topic is sparse. The aim of this study is to explore potential clients’ and assistants’ views, needs, experiences, opinions, and concerns about sexual assistance (SA) in Italy. Twenty-two semi-structured interviews were conducted with 12 people with a congenital physical disability and 10 would-be assistants. A Grounded Theory approach was used to analyze data. Participants with disabilities considered SA useful. Despite most of them having unfulfilled sexual needs, they would prefer to have their sexual needs met within a romantic relationship. Would-be assistants constructed themselves as people who have a “natural aptitude to being useful”. Results suggest that SA services might represent an opportunity for people with disabilities to discover new ways to satisfy their personal needs and to live more autonomously while, at the same time, allowing would-be sexual assistants to fulfill their desire to be helpful. Nevertheless, the use of SA is likely to only be a part of the answer to fulfilling the sexual needs of people with disabilities.